The long-term goal of the proposed research program is to understand the unique contribution of prefrontal pathways in circuits associated with emotion, cognition and memory. Behavioral and functional studies in human and non-human primates suggest that the executive functions of the prefrontal cortex are guided by interaction with structures associated with emotions. The goal of the proposed studies is to investigate the synaptology of pathways that link posterior orbitofrontal and anterior cingulate cortices with the amygdala, temporal cortices and thalamic structures, which have a key role in emotional processes and memory. The proposed studies will focus on the largely unexplored issues of the synaptic interaction of prefrontal pathways with inhibitory systems, and the concerted projections of multiple pathways that participate in distinct aspects of emotional processing. The proposed studies are guided by the working hypothesis that the posterior orbitofrontal cortex and the anterior cingulate have specialized connections with distinct inhibitory and excitatory systems in the amygdala, temporal and thalamic structures, suggesting both specialized and synergistic roles in motivated behavior. This hypothesis will be tested by investigating: the differential synaptic organization of posterior orbitofrontal and anterior cingulate pathways in the amygdala; concerted projections from posterior orbitofrontal, anterior cingulate and the amygdala to memory-related temporal cortices, that may enhance memory for emotionally salient stimuli; the sequential projections of the amygdala to posterior orbitofrontal cortex through the thalamic mediodorsal nucleus, and their combined projections to excitatory and inhibitory systems in prefrontal cortex, that may enhance processing of emotionally relevant signals and reduce noise; and the synaptic interaction of the amygdala, posterior orbitofrontal cortex and the mediodorsal thalamic nucleus on the inhibitory thalamic reticular nucleus, which gates signals between the thalamus and cortex, and may allow emotionally salient stimuli to gain rapid access to the cortex. Multiple pathways will be labeled with distinct neural tracers, combined with double or triple labeling to map pathways and inhibitory neurons and their synaptic interactions, using quantitative analyses and three-dimensional reconstruction of synapses. Findings from this study will form the basis to understand the specific role of prefrontal pathways in excitatory and inhibitory control within an emotional context, in processes that are disrupted in psychiatric diseases, including post traumatic stress disorder, obsessive compulsive disorder and depression. PUBLIC HEALTH RELEVANCE: The orbitofrontal cortex and the anterior cingulate have a pivotal role in emotions, and their projections to specialized inhibitory and excitatory systems in the amygdala, temporal memory-related structures and the thalamus, have a key role in focusing attention on emotionally salient events, and in establishing, remembering and eventually extinguishing emotional responses, such as fear. The balance of excitation and inhibition is disrupted in several psychiatric diseases characterized by anxiety, including post-traumatic stress disorder, panic disorder, obsessive-compulsive disorder and depression, affecting the systems under study. The proposed studies will probe the organization and specificity of these important circuits at high resolution at the level of systems, neurons, synapses and receptors, which is prerequisite for the development of therapeutic methods with actions on these pathways, such as the recent clinical trial of D-cycloserine for the treatment of post-traumatic stress disorder.